Parkinson's disease (PD) is a progressive neurodegenerative disease whose primary clinical manifestation includes motor disorders such as dyskinesia, resting tremor, rigidity, and gait disturbance. PD is characterized by the loss of dopamine neurons in the substantia nigra pars compacta and the presence of inclusion bodies in the surviving neurons of the same region. Progression of these inclusion bodies to the various regions outside the midbrain may account for the abundance of the secondary symptoms commonly observed in PD patients, such as depression, dementia, and various autonomic and sensory dysfunctions.
PD affects more than 4 million people worldwide and is becoming more and more prevalent as the population ages. The diagnosis of PD mostly relies on clinical symptoms. Since the disease is characterized by a long pre-clinical phase, it is often diagnosed only after irreversible damage has already occurred. In specialist clinics, the positive predictive value of the clinical diagnosis of idiopathic PD can reach 99% with 91% sensitivity. However, outside the specialist setting, the predictive value is considerably lower (Hughes et al., Brain, 2002, 125, 861). PD progression is monitored using the Hoehn and Yahr (HY) scale (Hoehn et al., Neurology, 1967, 17, 427). Progressively higher stages correlate with neuroimaging studies of dopaminergic loss, and high correlations exist between the HY scale and some standardized scales of motor impairment, disability, and other parameters which impair the quality of life (Goetz et al., Mov. Disord., 2004, 19, 1020).
Correct and early diagnosis currently depends on the expertise of the treating physician. Although important progress has been made in biomarker research for PD, no validated biomarker is available to date (Michell et al., Metabolomics, 2008, 4, 191; Ahmed et al., J. Biomed. Sci., 2009, 16, 63; Bogdanov et al., Brain, 2008, 131, 389; Quinones et al., Neurobiol. Dis., 2009, 35, 165; Greenberg et al., Electrophoresis, 2009, 30, 1235).
Recent studies indicate that the metabolic changes which are associated with PD may be traced by metabolomic profiling (i.e. the identification of patterns of metabolomic biomarkers that together provide a characteristic fingerprint) in blood or urine samples. PD signatures and sets of relevant biomarkers (mostly derivatives of alkylamines, organic acids, and sugar alcohols) were derived through pattern recognition analysis (Michell et al., Metabolomics, 2008, 4, 191; Ahmed et al., J. Biomed. Sci., 2009, 16, 63; Bogdanov et al., Brain, 2008, 131, 389; Quinones et al., Neurobiol. Dis., 2009, 35, 165; Baykal et al., Metabolomics, 2008, 4, 347). The results of the plasma analysis show promising results for the development of early-stage diagnostics, and indicate that there might be a connection between disease progression and metabolite variation. However, blood sampling is invasive and requires time consuming laboratory procedures prior to analysis (e.g. agitation, incubation etc.).
WO 2010/066000 discloses a method for predicting the susceptibility of a subject to a mental or neurodegenerative disorder, including PD, the method comprising: (a) obtaining one or more biological samples from the subject; (b) determining the levels of one or more biomarkers in the sample, wherein the biomarkers are selected from pyrroles, histamine, methionine adenosyltransferase (MAT) activity, homocysteine, copper and zinc; and (c) comparing the level(s) of the biomarker(s) determined in (b) with the level(s) of said biomarker(s) from one or more control samples, wherein abnormal levels of the one or more biomarkers in the sample(s) from the subject compared to the one or more control samples is predictive of susceptibility of the subject to a mental or neurodegenerative disorder.
WO 2000/000636 discloses a method of determining the in vivo conversion activity of a Class I, II or III gateway enzyme, said method comprising the steps of: identifying a Class I, II or III gateway enzyme to be assayed; selecting a labelled metaprobe for said enzyme, said metaprobe being selected so that when acted upon by said enzyme, at least one labelled end product that is directly detectable is produced; administering to a patient a defined amount of said labelled metaprobe; and determining the extent of conversion of said metaprobe to said labelled end product by said enzyme.
WO 2008/124187 discloses a method for diagnosis or monitoring a disease or condition in an individual comprising: (a) collecting one or more biological sample from said individual, wherein the biological sample(s) contain proteins, lipids and nucleic acids of the individual; (b) analyzing the proteins and/or lipids from a biological sample to determine selective metabolites and oxidation products of arachidonic acid (AHA), docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA); wherein said analyzing results in a metabolic determination of oxidative stress and lipids; and (c) analyzing the nucleic acids from a biological sample to determine the genotype and/or expression of genes involved in oxidative stress and/or lipid metabolism; wherein the existence or severity of a disease or condition is determined.
WO 2009/144725 to one of the inventors of the present application discloses a system for detecting volatile organic compounds derived from a breath sample, the system comprising: (a) an apparatus comprising an array of chemically sensitive sensors of single walled carbon nanotubes coated with non-polar small organic molecules, and (b) a processing unit comprising a learning and pattern recognition analyzer wherein the learning and pattern recognition analyzer receives sensor output signals and compares them to stored data.
WO 2010/064239 to one of the inventors of the present application discloses a system comprising an array of sensors for measuring volatile organic compounds as biomarkers for diagnosis, prognosis and monitoring of renal insufficiencies, the system comprises an array of sensors comprising a (semi-) conductive random network of single-walled carbon nanotubes (SWCNTs) coated with an organic coating which comprises oligomers or polymers modified with at least one polar functional group, in conjunction with learning and pattern recognition algorithms.
WO 2009/066293 to one of the inventors of the present application discloses an apparatus comprising at least one chemically sensitive sensor for detecting volatile and non-volatile compounds, wherein the chemically sensitive sensor comprises cubic nanoparticle conductive cores capped with an organic coating. Methods of use thereof in identifying various disease biomarkers, and in food quality and environmental control are disclosed.
WO 2010/079490 to one of the inventors of the present application discloses a sensor array for detecting biomarkers for cancer in breath samples. The sensor array is based on 2D films or 3D assemblies of conductive nanoparticles capped with an organic coating wherein the nanoparticles are characterized by a narrow size distribution.
WO 2003/094932 discloses the use of carbon monoxide (CO) as a biomarker and therapeutic agent of conditions and disease states including, inter alia, Parkinson's disease.
WO 2000/061002 discloses a method for the assessment of psychiatric or neurological conditions, including PD, the method comprising determining the presence and/or amount of ethane or butane in the expired breath of the patient.
At present, no simple and reliable technique is available for the early diagnosis of PD. Additionally, there remains an unmet need for monitoring Parkinson's disease progression using breath biomarkers thus affording adequate PD management.